Many drugs are extensively and reversibly bound to plasma proteins. Recent evidence has shown that, unlike anionic drugs which bind predominantly to albumin, some cationic drugs such as the cardiac-active drugs - propranolol, quinidine, lidocaine and the tricyclic antidepressants - are strongly bound to Alpha 1-acid glycoprotein and lipoproteins. Data exist relating binding of cardiac-active drugs to individual proteins. There has been, however, no comprehensive study of protein binding by the calcium channel blockers, especially by lipoproteins. This project will investigate the ability of plasma proteins to bind calcium channel blockers (verapamil, nifedipine, diltiazem) and propranolol. Emphasis will be placed on binding to Alpha 1-acid glycoprotein and lipoproteins. Using equilibrium dialysis for binding studies, bound and free drug concentrations will be obtained. Binding curves will be constructed by plotting bound against free drug concentrations. The mechanism of individual protein-drug interactions will be examined initially. The study will then be extended to the complex protein environment of plasma. Since only free drug is pharmacologically active, alterations in plasma protein matrix and protein binding will affect the intensity and duration of drug action and can also lead to misinterpretation of total serum drug concentration as reported by clinical laboratories. Thus the study has important implications for the management of high risk patients who have suffered acute tissue injury such as myocardial infarction and coronary bypass surgery, since changes in "acute phase" protein reactants like Alpha\1-acid glycoprotein and lipoprotein accompany such injury. Preliminary data suggest higher relative binding of diltiazem to low density and high density lipoproteins and Alpha 1-acid glycoprotein than to albumin. Extensive drug binding to lipoproteins suggests that binding could be highly variable in patients with marked elevations in plasma lipoprotein levels due to familial or acquired forms of hyperlipoproteinemias. The concept of lipoproteins as transport molecules may need to be expanded to consider the important association of drug and lipoprotein metabolism.